Genetic engineering technology has recently
generated techniques for making specific and precise alterations to
the genetic composition of crops grown as food for humans and
animals. These advances should facilitate the development of crops
with enhanced resistance to diseases, pests and bad weather,
improved tolerance of environmentally safer herbicides, and greater
nutritional value. However, the very power of these techniques has
raised fears of potential ecological catastrophe, as well as
religious and aesthetic questions that arise from the prospect of
vegetables containing genes ultimately derived from fish and
animals. This essay briefly reviews the nature of the technology
and its potential benefits and risks. It then discusses the
regulatory framework with particular emphasis on the regulatory
strategy adopted by FDA. Finally, it suggests that FDA's stance,
while legally and scientifically defensible, is strategically
misconceived in that stricter regulation would promote public
acceptance of this technology.

Nature of the technology

Mankind has been manipulating food crops for
millennia. All modem staple crops are derived from originally wild
varieties domesticated by man and propagated far beyond their
natural ecological niches. Human intervention was limited at first
to artificial selection of variants occurring through natural
mutation and gene rearrangement. The discovery of Mendelian
genetics in the last century made possible rationally directed
breeding programs. Though scientific principles now informed the
selection of hybrids and generation of true-breeding strains,
traditional breeding still depended on naturally occurring
variations; hybrids could be generated only by

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crossing variants of the same species.
Nevertheless, traditional breeding techniques have resulted in
dramatic changes in foods: for instance, a small berry native to
Asia ("chinese gooseberry") was transformed into the large
"kiwifruit" now popular in America and Europe.1

Biotechnology has been applied to food crops in two
successive waves. "Old biotechnology" employs artificial techniques
to increase variation in target plants (so as to enhance the
likelihood of finding a desirable trait) and to facilitate transfer
of genes across the species barrier. Thus, random mutations are
induced by treatment with chemicals or irradiation (mutagenesis) or
facilitated by cloning cells from cultures of callus or leaf
(somaclonal variation). Fertile progeny can be derived from "wide
crosses" (between different species) by techniques such as embryo
rescue and chromosomal doubling •2

"New biotechnology" uses genetic engineering
techniques to select genes encoding desirable traits and introduce
them into cells of host plants in which these traits are desired.
By culturing whole plants from these altered cells, transgenic
plant lines can be produced that contain the inserted gene in every
cell and transmit the inserted gene to every successive generation.
These genetic engineering techniques represent a powerful advance
in two respects. First, it is now possible to select and insert a
desirable gene without simultaneously introducing other,
undesirable traits that must later be eliminated through
traditional breeding (or tolerated). Second, the species barrier is
eradicated. Plants can receive genes from viruses, bacteria, other
plants or animals (including man).

The inserted genetic material is laboratory-made
and consists of the gene encoding the desired trait together with
additional genetic material to achieve permanent incorporation into
cells of the host plant and efficient expression of the desired
trait. Currently, these "workhorse" genes are derived from bacteria
that naturally infect plants --
a fact that has regulatory consequences. In

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addition, current technology requires insertion of
an additional gene to permit selection of those few altered cells
that receive functioning inserted genetic material for further
study. After this initial selection, the marker gene plays no
useful role, but nevertheless continues functioning in every cell
of every plant in every subsequent generation. Since the marker
currently used is an antibiotic-resistance gene derived from a
bacterium that commonly causes disease in humans, this aspect of
the technique presents a regulatory issue.

Potential benefits ofthe
technology

Genetic engineering techniques vastly expand the
repertoire of alterations that are feasible in food crops. By 1992,
over 30 transgenic crops were being field tested.3 The
front runner, the Flavr Savr tomato developed by Calgene,
illustrates the commercial potential of even elementary
modifications. In order to slow down the process of ripening and
softening that eventually renders tomatoes unfit for sale, Calgene
isolated the gene encoding an enzyme responsible for this process
(polygalacturonase, PG) and inserted it backwards (antisense). When
the normal gene becomes active during ripening and produces the
chemical message (mRNA) that would normally cause the cells to make
the PG enzyme, this message complexes with the product of the
antisense gene and is rapidly destroyed. Since the cells are unable
to make PG, softening is greatly retarded, and spoilage of the
vine-ripened tomatoes correspondingly reduced. The firmer texture
of these tomatoes is also valued in processing. In several ways,
this is an ideal test product. The desired trait depends not on
introducing a protein derived from other plants or from animals,
but on preventing the appearance of a tomato protein. Calgene has
subjected its product to extensive testing, including full
characterization of the inserted genetic construct to prove its
stability and extensive toxicological analysis on the individual
tomato variants developed.

Other proposed applications are even more ambitious
and offer tantalizing prospects for

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solving ecological and nutritional problems of both
the industrialized and the developing world.4 Crops can
be made resistant to insect pests, e.g. by introducing genes
encoding a selectively toxic bacterial protein (the Bt protein)
that does not affect mammals, fish, plants or beneficial insects.
Resistance could be conferred against plant viruses and against
adverse weather conditions such as frost and changes in
temperature. There are proposals to develop salt-tolerant crops
that could be grown in arid regions upon irrigation with pure or
partly desalinized sea-water. Altered feed crops are being
developed with increased amounts of essential amino acids such as
lysine and methionine. Similar modifications to staple crops could
do much to alleviate protein malnutrition in the developing world.
Foods being modified to combat diseases of industrialized nations
include strawberries rich in the cancer-protective agent ellagic
acid, and rapeseed enriched in unsaturated fats as a source of
healthier canola oil. Crops that can fix nitrogen (or that harbor
nitrogen-fixing bacteria, as legumes do) would decrease the need
for artificial fertilizers, benefiting the ecology of
industrialized nations and the food supply of developing ones.
Crops that resist broad-spectrum herbicides will permit the use of
environmentally friendly herbicides chosen for their rapid
disappearance from the soil rather than their narrow killing
spectrum.

Contrary to the claims of some critics, the
economics of genetic engineering suggest benefits for the
developing world. The nature of the technology requires great
sophistication to produce transgenic plants but not to exploit
them. Crops could be custom-made in western laboratories and the
seeds distributed directly to farmers in the developing world,
making this a highly sophisticated yet fully appropriate
technology. Presumably western donor governments would be disposed
to fund aid projects that directly benefitted not merely their
domestic economies but also the biotechnology sector they have
targeted for promotion.

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Potential risks ofthe technology

(I) Risks arising from cultivation

Genetic material in transgenic crops is transmitted
to successive generations of the transgenic crop itself and has the
potential to spread through cross-pollination to native
(non-transgenic) variants of the same species (whether cultivated
or wild) and to other sexually compatible species.3
Contamination of native seeds with seeds from transgenic variants
will produce mixed crops in the next generation; it is likely that
native and transgenic seeds and plants will be indistinguishable to
the native eye. In this way, transgenic crops could enter the food
supply unrecognized, frustrating attempts to track and label
them.

Inserted genetic material could also be acquired by
bacteria or viruses that infect the transgenic plants (horizontal
transfer); these micro-organisms could conceivably act as vectors
to convey the genetic constructs to other plants. Though
theoretically valid, these events are probably very infrequent;
moreover, the same potential exists for genes native to the plant.
The one exception to this complacent assessment is the antibiotic
resistance gene inserted as a marker for the genetically altered
cells. This gene is derived from bacteria, which transfer
antibiotic resistance genes amongst one another. Antibiotic
resistance would confer a selective advantage on bacteria in
settings where use of that antibiotic is widespread. USDA has
accepted calculations, based on a worst case scenario, that even if
such transfers occur the antibiotic-resistant soil bacteria that
result would represent 1.4 x 10" of the resistant microbes already
present.6

Genetic manipulation of plants may confer a
competitive advantage and create the potential for growth as a
weed. This is likeliest with alterations that confer resistance to
pests or chemicals or reduce the need for fertilizers, and is a
major consideration in USDA regulatory policy.

Many plants contain toxic substances. Most edible
plants, when ripe, have low enough levels of poisons to permit safe
ingestion; in some (such as cassava and some legumes) proper
preparation is required before the food can be safely eaten.
Genetic manipulation could introduce toxic substances or increase
their concentration by a variety of mechanisms. Interfering with
the normal ripening process could prevent the normal decrease in
toxic substances that accompanies ripening. For instance, tomatoes
belong to the same plant family as the Deadly Nightshade; the Flavr
Savr tomato was specifically tested for tomatine and other
potentially poisonous glykoalkaloids in ripe and green fruit, for
each line to be commercialized.7 Introduced substances
that are innocuous in the donor plant could be metabolized
differently by the host, with toxic results. The introduced genetic
material, which by current techniques is inserted at a random site
in the host's genes, may by chance inactivate a metabolic pathway
required to neutralize a toxic intermediate or may reactivate a
toxic pathway silenced during evolution.

By similar mechanisms, genetic manipulation may
reduce the nutritional value of food either by altering the level
or bioavailability of important nutrients or by altering the
chemical nature of important nutrients. If this technology had
arisen before we realized the importance of saturated fats in
contributing to heart disease and certain cancers, it is unlikely
that transgenic plants would have been monitored for alterations in
these components; one can only speculate about other aspects of
nutrition that we currently fail to monitor through ignorance.

Food allergy is well recognized, but imperfectly
understood. It is highly idiosyncratic. The propensity for allergic
reactions runs in families, but the provoking allergens differ for
each

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individual and are discovered by trial and error.
Allergic individuals are counselled to avoid foods known to be
allergenic to them. Some foods (e.g. shellfish, nuts) commonly
provoke allergic reactions. In some cases the provoking allergen
-- generally a protein
-- is known (e.g. gluten in
wheat), but in most cases it is not. While tests with allergic
volunteers can identify major allergenic components, the
idiosyncratic nature of allergy dictates that a food can never be
pronounced free of introduced allergens for an particular allergic
individual. Allergic consumers always eat any new food at the risk
of provoking a reaction; only a warning that the food has been
genetically engineered (and disclosing the origin of any protein
introduced) can trigger the appropriate precautions.

Potential interference with antibiotics has become
a heated topic. Currently technology requires the introduction of
an antibiotic resistance gene as a marker for transfected cells.
The 30 products closest to market use the kad gene (which
encodes the enzyme kanamycin phosphotransferase II and confers
resistance to medically important antibiotics such as kanamycin and
neomycin). Both the kanr gene and its enzyme product will be
present in food derived from the transgemc plants, raising the
possibility that the enzyme may interfere with orally administered
kanamycin or neomycin, and that the gene may be transferred to gut
bacteria and make them resistant. FDA appears to accept that the
enzyme represents little danger, since it will be digested like any
other protein and even while intact would not be able to act in the
chemical environment of the gut. Moreover, these antibiotics are
poorly absorbed and are rarely given orally.' FDA responded less
convincingly to the issue raised by the gene when it pointed to
widespread topical use of neomycin-containing ointments as a major
factor in inducing resistance. The agency has not explained why
these ointments should not be restricted from OTC use rather than
used as the predicate for promoting yet more resistance to an
important group of antibiotics, commonly used

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for intravenous therapy of life-threatening
infections.

(3) Religious, aesthetic and ecological
concerns

Transferring genes across species raises religious
and aesthetic concerns. Consumers who avoid certain species on
religious grounds (pigs for Muslims, cows for Hindus, various
species of animals, fish and crustaceans for Jews) or for moral or
aesthetic reasons (vegetarians, vegans) must confront the issues
raises by genetically engineered plants that express genes
originally derived from animal species. Most people might feel
qualms about eating plants whose genes were partly human. FDA has
taken the position that scientists do not infuse the plant with the
original genes that were removed from the animal and that there is
no scientific evidence that such genetic alterations change the
essential nature of the plant or confer "animal-like"
characteristics.9 The agency therefore concludes that
information on the label disclosing the use of genetic engineering
and indicating the transgene's origin would not be material, no
matter how earnestly consumers desire it. This is a callous and glib response to issues that are
religious and aesthetic rather than scientific and on which FDA
manifestly lacks expertise.

Critics have raised concerns about the economic
impact of high technology crops that would benefit large
agricultural producers over small farmers, and industrialized
nations over third world agricultural exporters. Commentators have
pointed to secondary ecological effects such as promoting increased
use of toxic chemicals'0 and reducing ecological
diversity."

Regulatory strategy ofUSDA

Regulation by USDA is aimed at protecting
agriculture from harmful effects of genetically engineered crops,
concerns distinct from their regulation as food. However,
comparison of the regulatory strategy of USDA and FDA reveals
distinctly different approaches by two agencies both eager to
promote this technology and reluctant to burden it with unnecessary
regulation. Despite

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FDA's primary mandate to promote the safety of the
food supply, it is USDA that adopted the more active monitoring
role. Paradoxically, it appears that closer regulation along the
USDA model may promote rather than retard this new industry.

USDA has asserted jurisdiction over transgenic
crops under the Federal Plant Pest Act, 7 U.S.C. §lSOaa-lSOjj
and the Plant Quarantine Act, 7 U.S.C. §§151-164a,
166~l67I2. This jurisdiction is based primarily on the presence of
inserted genetic material derived originally from bacteria or
viruses that infect plants. In general, prior approval (by
obtaining a permit) is needed before a genetically engineered plant
can be introduced into agriculture, whether for field testing or
commercial farming. However, certain host species have been
designated as having negligible risk for inadvertent transfer of
inserted genes to other crops. Genetically engineered variants of
these species (corn, cotton, potato, soybean, tobacco, tomato) can
be introduced without prior approval provided USDA is notified in
the prescribed form. Moreover, an interested party can petition for
deregulation of a particular genetically engineered plant. Calgene
successfully petitioned for deregulation of its Flavr Savr tomato
under this procedure.'3

USDA has adopted a flexible regulatory strategy
that avoids blanket determinations early in the history of an
emerging new technology. For most crops, the agency requires
premarket approval. For some species with lower risk, the agency is
willing to play a monitoring role. Where the accumulated data
justifies it, the agency will grant deregulated status.

Regulatory strategy ofFDA

FDA's regulatory strategy is founded on a
science-based approach and on the premise that genetic engineering
is simply an extension of traditional breeding and of "old
biotechnology" by application of new techniques. By regulating the
products of genetic engineering and declining to regulate the
process, FDA seeks to incorporate genetic engineering into its
existing regulatory

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framework, with minor
modifications.14

FDA relies primarily on § 402(a)(l) of
the Food, Drug, And Cosmetic Act (EDGA) to regulate food from
genetically engineered plants. Any constituent of these foods that
is newly introduced or expressed at higher levels following the
manipulation is regarded as an "added substance" within the meaning
of this section and thus regulated under the strict "may render
injurious to health" standard. Food is adulterated if there is a
"reasonable possibility" that its consumption will be injurious to
health.'5 This standard applies whether the alteration
is intentional or inadvertent, and the producer bears legal
responsibility for meeting it. FDA's policy is to guide the
industry by formal guidelines and informal consultation, while
reserving its formidable civil and criminal enforcement powers
until breaches have occurred.'6 The agency thus intends
to play a consultative and policing rather than a licensing
role.

Any substance intended as a food component, unless
generally regarded as safe (GRAS), is subject to regulation under
§§ 201(s) & 409 as a food additive. Food
additives are banned unless exempted by regulation -- i.e. they are subject to licensing by
FDA. The agency's reluctance to play an extensive licensing role is
evident in its published guidelines.

First, FDA adopts a narrow interpretation of the
intended use test of § 201(s). The statutory language
covers "any substance the intended use of which results or may
reasonably be expected to result, directly or indirectly, in
its becoming a component or otherwise affecting the
characteristics of any food..." Despite this very broad
language, FDA treats as potential food additives only the
transferred genetic material and the in1~nd~l expression
product.'7 Second, FDA has adopted a broad view of GRAS.
It states categorically that "[i]ntroduced nucleic acids [i.e.
foreign genetic material, in and of themselves, do not raise safety
concerns." and are presumed GRAS.'8 This is surprising
in view of the concern that antibiotic resistance genes

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ingested in food may be transferred to gut bacteria
and confer antibiotic resistance. The agency will presume as GRAS
any introduced substance that is present in currently consumed
foods at generally comparable or greater levels. However, any
significant modification in structure, function or composition from
"substances found currently in food" would raise a GRAS issue.
Modifications are thus tested against substances found ~wx~nUyiaf~l
and not substances found ordinarily in the unmodified host
food . FDA provides extensive guidance in recommending safety
issues to be addressed, but once again leaves compliance with the
food producer. There is no requirement for notification or prior
approval; once again, the agency envisages a more limited
consultative and policing role.

FDA has also shown reluctance to impose strict
labeling requirements for genetically engineered foods. The agency
asserts its broad power under § 403(i) combined with
§§ 403(a) & 201(n) to require disclosure not
only of a food's common or usual name, but also of any material
difference from foods traditionally described by that name and of
any material safety or usage issue. Yet FDA does not require
disclosure that a food is genetically engineered, nor that proteins
derived from other (donor) foods are present unless the donor food
commonly produces allergic reactions. Even then, no disclosure is
required if there is sufficient information showing that the
(major) allergenic components of the donor food are known and are
not present in the proteins introduced into the host
food.'9 The agency takes the view that genetic
engineering techniques are merely extensions of traditional
breeding methods and that the resulting foods do not differ from
other foods in any meaningful or uniform way.

Evaluation of FDA's regulatory strategy

While FDA's general approach is scientifically
sound, and its restrained approach undoubtedly within its statutory
discretion, the agency appears to have erred on the side of
under-

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regulation, to the detriment of the industry it
wishes to encourage.

The agency's decision to incorporate genetically
engineered food into its existing regulatory structure seems wise.
The very broad discretion and enforcement powers granted in the
FDCA would permit virtually whatever regulation the agency wished
to impose. By asserting a broad interpretation of the intended use
test of § 201(s), together with a strict view of GRAS,
FDA could impose a premarket approval regime for all genetically
engineered foods. Similarly, its discretion on what disclosures are
material for labeling is in practice unreviewable. By eschewing a
request for new statutory powers, FDA avoided forcing on Congress a
sensitive and emotive issue on which the general public has not yet
had time to frame a considered opinion. Any Congressional action
could scarcely have given FDA more effective powers; the only
change likely to arise from new legislation would be an attempt to
impose a stricter regulatory duty on the agency. If at all
effective, the result would have been to lock in a rigid and
inflexible regulatory regime.

Since FDA is operating within the realm of
discretion, it should consider the following changes to its
regulatory strategy:

(1) A more subtly tailored licensing and
notification regime.

USDA provides a regulatory model which is readily
applicable to genetically engineered foods. While it is impractical
and unnecessary to regulate each individual food item, the number
of new plants is much more limited and could readily be regulated
by a combined licensing and notification scheme. Genetically
engineered modifications would in general require premarket
approval. Where FDA was satisfied that a commonly used technique
was safe (such as using the k~~d gene as an antibiotic
resistance marker) it could be designated as approved and exempted
from licensing. Even greater flexibility could be achieved by
designating standards rather than individual genes (e.g. to ensure
stable integration of the new genetic material in the host); this
would approach

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the flexibility of the present guidelines. In all
cases, however, the agency should insist on notification and should
maintain a database of foods containing genetically engineered
components. The agency should also consider imposing monitoring
requirements for adverse reactions associated with the new
products.

It is true, as FDA asserts, that genetic
engineering is an extension of traditional breeding and other
techniques, and that any change to a food crop may produce
unintended effects. However, this does not justify turning a blind
regulatory eye to possible adverse effects from one of the most
powerful technologies known to mankind, and one that could rapidly
and profoundly transform the human diet. Monitoring suspected
allergic and other adverse reactions could give early warning of
unforeseen problems and would allow FDA to forestall some future
crisis that might jeopardize public acceptance of all genetically
engineered foods.

Given the extensive consultation envisaged by FDA,
and conducted with the pioneering products currently approaching
market, this new regime would not greatly increase the industry's
regulatory burden. Indeed, recent developments suggest that the
industry might prefer tighter regulation to help it overcome public
hesitancy about the new technology. The perception, of unbridled
deregulation is deeply damaging to this emerging sector, as the FDA
Commissioner franldy admitted?" Moreover, Calgene has requested
that FDA regulate the ka~ gene and its enzyme product as
food additives in order to help correct "misunderstanding by the
public as to the scope and rigor of FDA's review of new
[genetically engineered] food products[,]...~ underscore the
adequacy of the FDA policy and provide confidence to the public.
..."21 The potential for adverse public reaction was
underscored when prominent restauranteurs announced a boycott of
genetically engineered foods, and when Campbell Soup Co. canceled
plans to use the Flavr Savr tomato, apparently in response to
public pressure.

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(2) Stricter labeling requirements

FDA has not persuasively justified its refusal to
treat the fact that a food is genetically engineered, and the
species of origin of the genetically introduced protein as material
facts requiring disclosure. Consumers with religious, moral or
aesthetic scruples are entitled to decide for themselves whether
the "essential nature" of a food has been altered, whatever FDA
concludes. Consumers who are allergic to some foods are entitled to
fair warning that an apparently familiar food may contain new
ingredients, so that they may take appropriate precautions.
Fortunately, FDA appears to be rethinking its position in the light
of comments responding to its 1992 Statement of Policy.~

Calgene's marketing plans illustrate the
feasibility of labeling genetically engineered fruits and
vegetables, since the company intends to mark each tomato with a
circular label. The proposed wording, however, illustrates the need
for regulation. The label will identify the product as "Macgregor's
Tomatoes. Grown From Flavr Savr Seeds." Point of sale information
will disclose use of "the latest developments in genetic
engineering, tomato plant breeding, and farming" as well as
insertion of "a gene which makes a naturally occurring protein
[that] makes Flavr Savr seeds resistant to kanamycin contained in
our test medium. "23 Taken as
whole, this seems fair. Without the point of sale information,
however, the label's folksy name would be misleading. Without
regulatory deterrence, unscrupulous producers (or retailers) might
be tempted to omit disclosing the use of genetic engineering,
especially if such products encounter consumer resistance.

(3) Imposing Current Good Manufacturing Practice
requirements

FDA has asserted the power under § 70
1(a) to impose CGMP requirements for food manufacturing, processing
and storage and has used its authority to impose recordkeeping
duties~ This section provides an alternative source of authority
for requiring producers and retailers to keep

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track of genetically engineered foods, whether sold
as raw produce or incorporated into processed foods. This authority
could also be used to impose technical standards for insertion of
genetic material (e.g. stable insertion of well-characterized
constructs) even if FDA wishes to avoid treating these components
as additives.

~Qn~Qn

In framing a regulatory response to new
technologies that affect the food supply, FDA must deal not only
with legal and scientific issues, but also with popular
perceptions. The public holds the agency in high regard and trusts
it to ensure the safety and accurate identification of foods. This
mandate the agency must not only discharge, but also be seen to
discharge. FDA's present approach to genetically engineered plants
is scientifically and legally defensible, but takes too little
account of public perceptions. In seeking to encourage the food
biotechnology industry, FDA is harming it through
under-regulation.

16. Under § 406, FDA has power to
establish tolerances for "poisonous or deleterious substance[s that
are] required in the production [of a food or that] cannot be
avoided by good manufacturing process .
. ." The agency has avoided using these powers on this
issue.

17. 57 Fed. Reg. at 22,990.

18. 57 Fed. Reg. at 22,990, 23,004.

19. ~ 57 Fed. reg. at 22,991.

20. ~ Food Chemical News, Apr. 26, 1993 at 13,
reporting Dr. David Kessler's remarks on the reduction of public
confidence in FDA's food biotechnology policy that arose through
association with the Council on Competitiveness. "Everyone would
have been better served if